BACKGROUND The amygdala is a central component of the neural circuitry that underlies fear learning. N-methyl-D-aspartate receptor-dependent plasticity in the amygdala is required for pavlovian fear conditioning and extinction. N-methyl-D-aspartate receptor activation requires the binding of a coagonist, D-serine, which is synthesized from L-serine by the neuronal enzyme serine racemase (SR). However, little is known about SR and D-serine function in the amygdala. METHODS We used immunohistochemical methods to characterize the cellular localization of SR and D-serine in the mouse and human amygdala. Using biochemical and molecular techniques, we determined whether trace fear conditioning and extinction engages the SR/D-serine system in the brain. D-serine was administered systemically to mice to evaluate its effect on fear extinction. Finally, we investigated whether the functional single nucleotide polymorphism rs4523957, which is an expression quantitative trait locus of the human serine racemase (SRR) gene, was associated with fear-related phenotypes in a highly traumatized human cohort. RESULTS We demonstrate that approximately half of the neurons in the amygdala express SR, including both excitatory and inhibitory neurons. We find that the acquisition and extinction of fear memory engages the SR/D-serine system in the mouse amygdala and that D-serine administration facilitates fear extinction. We also demonstrate that the SRR single nucleotide polymorphism, rs4523957, is associated with posttraumatic stress disorder in humans, consistent with the facilitatory effect of D-serine on fear extinction. CONCLUSIONS These new findings have important implications for understanding D-serine-mediated N-methyl-D-aspartate receptor plasticity in the amygdala and how this system could contribute to disorders with maladaptive fear circuitry.

中文翻译：

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杏仁核中的丝氨酸消旋酶和 D-丝氨酸动态参与恐惧学习

背景杏仁核是恐惧学习基础的神经回路的核心组成部分。杏仁核中 N-甲基-D-天冬氨酸受体依赖性可塑性是巴甫洛夫恐惧条件反射和灭绝所必需的。N-甲基-D-天冬氨酸受体激活需要与辅酶D-丝氨酸结合，D-丝氨酸是通过神经元酶丝氨酸消旋酶（SR）从L-丝氨酸合成的。然而，人们对杏仁核中的 SR 和 D-丝氨酸功能知之甚少。方法我们使用免疫组织化学方法来表征小鼠和人杏仁核中 SR 和 D-丝氨酸的细胞定位。使用生化和分子技术，我们确定了微量恐惧条件反射和灭绝是否与大脑中的 SR/D-丝氨酸系统有关。D-丝氨酸全身给药于小鼠以评估其对恐惧消退的影响。最后，我们研究了功能性单核苷酸多态性 rs4523957，它是人类丝氨酸消旋酶 (SRR) 基因的表达数量性状基因座，是否与高度创伤的人类队列中的恐惧相关表型相关。结果 我们证明杏仁核中大约一半的神经元表达 SR，包括兴奋性和抑制性神经元。我们发现恐惧记忆的获得和消退与小鼠杏仁核中的 SR/D-丝氨酸系统相关，并且 D-丝氨酸给药促进了恐惧消退。我们还证明了 SRR 单核苷酸多态性 rs4523957 与人类的创伤后应激障碍相关，这与 D-丝氨酸对恐惧消退的促进作用一致。